Benzyl-substituted carbamates and use thereof

ABSTRACT

The present application relates to novel benzyl-substituted carbamates, to processes for their preparation, to their use, alone or in combinations, for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular disorders.

The present application relates to novel benzyl-substituted carbamates,to processes for their preparation, to their use, alone or incombinations, for the treatment and/or prophylaxis of diseases and totheir use for preparing medicaments for the treatment and/or prophylaxisof diseases, especially for the treatment and/or prophylaxis ofcardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitrogenmonoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyse the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family known to date can be dividedinto two groups either according to structural features or according tothe type of ligands: the particulate guanylate cyclases which can bestimulated by natriuretic peptides, and the soluble guanylate cyclaseswhich can be stimulated by NO. The soluble guanylate cyclases consist oftwo subunits and very probably contain one heme per heterodimer, whichis part of the regulatory site. This is of central importance for theactivation mechanism. NO is able to bind to the iron atom of heme andthus markedly increase the activity of the enzyme. Heme-freepreparations cannot, by contrast, be stimulated by NO. Carbon monoxide(CO) is also able to bind to the central iron atom of heme, but thestimulation by CO is much less than that by NO.

By forming cGMP, and owing to the resulting regulation ofphosphodiesterases, ion channels and protein kinases, guanylate cyclaseplays an important role in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and platelet adhesion and in neuronal signaltransmission, and also in disorders which are based on a disruption ofthe abovementioned processes. Under pathophysiological conditions, theNO/cGMP system can be suppressed, which can lead, for example, tohypertension, platelet activation, increased cell proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, myocardial infarction, thromboses, stroke and sexualdysfunction.

Owing to the expected high efficiency and low level of side effects, apossible NO-independent treatment for such disorders by targeting thethe influence of the cGMP signal pathway in organisms is a promisingapproach.

Therapeutic stimulation of soluble guanylate cyclase has to date beenaccomplished using exclusively compounds such as organic nitrates, theeffect of which is based on NO. The latter is formed by bioconversionand activates soluble guanylate cyclase by attack at the central ironatom of heme. In addition to the side effects, the development oftolerance is one of the crucial disadvantages of this mode of treatment.

In recent years, some substances have been described which stimulatesoluble guanylate cyclase directly, i.e. without prior release of NO,such as, for example 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole[YC-1; Wu et al., Blood 84 (1994), 4226; Mulsch et al., Brit. J.Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol.Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettiboneet al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu etal., Brit. J. Pharmacol. 114 (1995), 1587] and various substitutedpyrazole derivatives (WO 98/16223).

WO 2008/031513 discloses inter alia 1H-pyrazolo[4,3-b]pyridines asstimulators of soluble guanylate cyclase for the treatment ofcardiovascular disorders. WO 2005/030121 describes fused pyrazoles forthe treatment of cancer diseases. WO 02/42300 describespyrazolopyridines having carbamate substituents for the treatment ofcardiovascular disorders. WO 2011/119518 and WO 2011/115804 disclosecarbamate-substituted pyrimidines for the treatment of cardiovasculardisorders.

It was an object of the present invention to provide novel substanceswhich act as potent stimulators of soluble guanylate cyclase and aretherefore suitable for treatment and/or prophylaxis of cardiovasculardisorders.

The present invention provides compounds of the general formula (I)

in which

-   -   R¹ represents hydrogen or fluorine,    -   R² represents hydrogen or amino,    -   R³ represents (C₁-C₄)-alkyl,    -   R⁴ represents hydrogen, (C₁-C₄)-alkyl or (C₁-C₄)-alkoxycarbonyl,    -   R⁵ represents phenyl, tetrahydronaphthalenyl, naphthyl or 5- to        10-membered heteroaryl,        -   where phenyl, tetrahydronaphthalenyl, naphthyl and 5- to            10-membered heteroaryl may be substituted by 1 to 3            substituents independently of one another selected from the            group consisting of halogen, nitro, cyano, difluoromethyl,            trifluormethyl, (C₁-C₆)-alkyl, hydroxy, difluoromethoxy,            trifluoromethoxy, (C₁-C₄)-alkoxy, amino,            mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino,            hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl, aminocarbonyl,            mono-(C₁-C₄)-alkylaminocarbonyl,            di-(C₁-C₄)-alkylaminocarbonyl,            (C₃-C₇)-cycloalkylaminocarbonyl, phenylsulfonylmethyl,            phenyl and phenoxy,            -   where (C₁-C₆)-alkyl may be substituted by one                substituent independently of one another selected from                the group consisting of hydroxycarbonyl and                (C₁-C₄)-alkoxycarbonyl,            -   and            -   where phenyl and phenoxy may be substituted by 1 to 3                substituents independently of one another selected from                the group consisting of halogen and cyano,    -   R⁶ represents (C₁-C₆)-alkyl or benzyl,        -   where (C₁-C₆)-alkyl is substituted by one trifluoromethyl            substituent,        -   where (C₁-C₆)-alkyl may be substituted by 1 to 3 fluorine            substituents,        -   and        -   where benzyl is substituted by 1 to 3 fluorine substituents,            and the N-oxides, salts, solvates, salts of N-oxides and            solvates of the N-oxides or salts thereof.

Inventive compounds are the compounds of the formula (I) and the salts,solvates and solvates of the salts thereof, the compounds encompassed byformula (I) of the formulae specified hereinafter and the salts,solvates and solvates of the salts thereof, and the compoundsencompassed by formula (I) and specified hereinafter as working examplesand the salts, solvates and solvates of the salts thereof, to the extentthat the compounds encompassed by formula (I) and specified hereinafterare not already salts, solvates and solvates of the salts.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the inventive compounds. Alsoencompassed are salts which are not themselves suitable forpharmaceutical applications but can be used, for example, for isolationor purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, formic acid, acetic acid, trifluoroacetic acid, propionic acid,lactic acid, tartaric acid, malic acid, citric acid, fumaric acid,maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases, by way of exampleand with preference alkali metal salts (e.g. sodium and potassiumsalts), alkaline earth metal salts (e.g. calcium and magnesium salts)and ammonium salts derived from ammonia or organic amines having 1 to 16carbon atoms, by way of example and with preference ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates refer to those forms of thecompounds according to the invention which, in the solid or liquidstate, form a complex by coordination with solvent molecules. Hydratesare a specific form of solvates in which the coordination is with water.Preferred solvates in the context of the present invention are hydrates.

The compounds according to the invention may, depending on theirstructure, exist in different stereoisomeric forms, i.e. in the form ofconfigurational isomers or else optionally as conformational isomers(enantiomers and/or diastereomers, including those in the case ofatropisomers). The present invention therefore encompasses theenantiomers and diastereomers, and the respective mixtures thereof. Thestereoisomerically uniform constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this, in particularHPLC chromatography on an achiral or chiral phase.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic number,but with a different atomic mass than that which occurs usually orpredominantly in nature. Examples of isotopes which can be incorporatedinto an inventive compound are those of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, suchas ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S,³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particularisotopic variants of an inventive compound, such as, more particularly,those in which one or more radioactive isotopes have been incorporated,may be of benefit, for example, for the study of the mechanism of actionor of the active ingredient distribution in the body; due to thecomparative ease of preparability and detectability, compounds labeledparticularly with ³H or ¹⁴C isotopes are suitable for this purpose.Furthermore, the incorporation of isotopes, for example of deuterium,can lead to particular therapeutic advantages as a consequence ofgreater metabolic stability of the compound, for example an extension ofthe half-life in the body or a reduction in the active dose required;such modifications of the compounds according to the invention maytherefore, in some cases, also constitute a preferred embodiment of thepresent invention. Isotopic variants of the compounds according to theinvention can be prepared by the processes known to those skilled in theart, for example by the methods described below and the proceduresdescribed in the working examples, by using corresponding isotopicmodifications of the respective reagents and/or starting compounds.

Moreover, the present invention also encompasses prodrugs of thecompounds according to the invention. Here, the term “prodrugs” refersto compounds which for their part can be biologically active orinactive, but are converted (for example metabolically orhydrolytically) into compounds according to the invention during theirdwell time in the body.

In the context of the present invention, the substituents, unlessspecified otherwise, are each defined as follows:

Alkyl in the context of the invention is a linear or branched alkylradical having 1 to 6 or 1 to 4 carbon atoms. Preferred examplesinclude: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl,1-ethylbutyl and 2-ethylbutyl.

Alkoxy in the context of the invention is a linear or branched alkoxyradical having 1 to 4 carbon atoms. Preferred examples include: methoxy,ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy andtert-butoxy.

Alkoxycarbonyl in the context of the invention is a linear or branchedalkoxy radical having 1 to 4 carbon atoms and a carbonyl group attachedto the oxygen. Preferred examples include: methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andtert-butoxycarbonyl.

Monoalkylamino in the context of the invention is an amino group havinga linear or branched alkyl substituent having 1 to 4 carbon atoms.Preferred examples include: methylamino, ethylamino, n-propylamino,isopropylamino and tert-butylamino.

Dialkylamino in the context of the invention is an amino group havingtwo identical or different, linear or branched alkyl substituents eachhaving 1 to 4 carbon atoms. Preferred examples include:N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino andN-tert-butyl-N-methylamino.

Monoalkylaminocarbonyl in the context of the invention is an amino groupwhich is attached via a carbonyl group and has a linear or branchedalkyl substituent having 1 to 4 carbon atoms. Preferred examplesinclude: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, n-butylaminocarbonyl andtert-butylaminocarbonyl.

Dialkylaminocarbonyl in the context of the invention is an amino groupwhich is attached via a carbonyl group and has two identical ordifferent, linear or branched alkyl substituents each having 1 to 4carbon atoms. Preferred examples include: N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl andN-tert-butyl-N-methylaminocarbonyl.

Cycloalkylaminocarbonyl in the context of the invention is an aminogroup which is attached via a carbonyl group and has a monocyclic,saturated carbocycle having 3 to 7 carbon atoms. Preferred examplesinclude: cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,cyclopentylaminocarbonyl, cyclohexylaminocarbonyl andcycloheptylaminocarbonyl.

Heteroaryl in the context of the invention is a monocyclic or optionallybicyclic aromatic heterocycle (heteroaromatic) which has a total of 5 to10 ring atoms, contains up to three identical or different ringheteroatoms from the group consisting of N, O and S and is attached viaa ring carbon atom or optionally via a ring nitrogen atom. Examplesinclude: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl,isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrazolo[3,4-b]pyridinyl. Preference is given to monocyclic 5- or6-membered heteroaryl radicals having up to three ring heteroatoms fromthe group consisting of N, O and S such as, for example, furyl, thienyl,thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl.

Halogen in the context of the invention is fluorine, chlorine, bromineand iodine.

If radicals in the compounds according to the invention are substituted,the radicals may be mono- or polysubstituted, unless specifiedotherwise. In the context of the present invention, all radicals whichoccur more than once are defined independently of one another.Substitution by one, two or three identical or different substituents ispreferred.

In the context of the present invention, preference is given tocompounds of the formula (I) in which

-   -   R¹ represents hydrogen or fluorine,    -   R² represents hydrogen or amino,    -   R³ represents (C₁-C₃)-alkyl,    -   R⁴ represents hydrogen or methyl,    -   R⁵ represents phenyl, thienyl, thiazolyl, pyridyl or quinolyl,        -   where phenyl, thienyl, thiazolyl, pyridyl and quinolyl may            be substituted by 1 to 3 substituents independently of one            another selected from the group consisting of fluorine,            chlorine, nitro, cyano, difluoromethyl, trifluoromethyl,            (C₁-C₆)-alkyl, hydroxy, difluoromethoxy, trifluoromethoxy,            methoxy, ethoxy, amino, methylamino, ethylamino,            dimethylamino, diethylamino, methoxycarbonyl,            ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl,            ethylaminocarbonyl, dimethylaminocarbonyl,            diethylaminocarbonyl, cyclopropylaminocarbonyl and            cyclobutylaminocarbonyl,            -   where (C₁-C₆)-alkyl may be substituted by one                substituent independently of one another selected from                the group consisting of hydroxycarbonyl, methoxycarbonyl                and ethoxycarbonyl,    -   R⁶ represents 3,3,3-trifluoroprop-1-yl,        3,3,4,4,4-pentafluorobut-1-yl or benzyl,        -   where benzyl is substituted by 1 or 2 fluorine substituents,            and the salts, solvates and solvates of the salts thereof.

Particular preference is given in the context of the present inventionto compounds of the formula (I) in which

-   -   R¹ represents hydrogen or fluorine,    -   R² represents hydrogen or amino,    -   R³ represents methyl, ethyl or isopropyl,    -   R⁴ represents hydrogen,    -   R⁵ represents phenyl,        -   where phenyl may be substituted by 1 fluorine substituent,    -   R⁶ represents 2-fluorobenzyl,        and the salts, solvates and solvates of the salts thereof.

Preference is also given in the context of the present invention tocompounds of the formula (I) in which R¹ is fluorine, and to the salts,solvates and solvates of the salts thereof.

Preference is also given in the context of the present invention tocompounds of the formula (I) in which R¹ is hydrogen, and to the salts,solvates and solvates of the salts thereof.

Preference is also given in the context of the present invention tocompounds of the formula (I) in which R⁶ is 2-fluorobenzyl, and to thesalts, solvates and solvates of the salts thereof.

Preference is also given in the context of the present invention tocompounds of the formula (I) in which

-   -   R⁵ represents phenyl,        -   where phenyl may be substituted by 1 fluorine substituent,            and the salts, solvates and solvates of the salts thereof.

Preference is also given in the context of the present invention tocompounds of the formula (I) in which

-   -   R⁶ represents 3,3,3-trifluoroprop-1-yl or        3,3,4,4,4-pentafluorobut-1-yl,        and the salts, solvates and solvates of the salts thereof.

The individual radical definitions specified in the particularcombinations or preferred combinations of radicals are, independently ofthe particular combinations of the radicals specified, also replaced asdesired by radical definitions of other combinations.

Particular preference is given to combinations of two or more of thepreferred ranges mentioned above.

The invention further provides a process for preparing the compounds ofthe formula (I) according to the invention, characterized in that acompound of the formula (II)

in which R¹, R² and R⁶ each have the meanings given above,is reacted in the presence of a suitable base with a compound of theformula (III)

in which R³ has the meaning given aboveto give a compound of the formula (IV)

in which R¹, R², R³ and R⁶ each have the meanings given above,this is then reacted with a compound of the formula (V)

in which R⁴ and R⁵ each have the meanings given above and

-   -   X¹ represents a suitable leaving group, for example mesylate,        tosylate or halogen, in particular bromine or iodine,        and        the resulting compounds of the formula (I) are, where        appropriate, converted with the appropriate (i) solvents        and/or (ii) acids or bases into their solvates, salts and/or        solvates of the salts.

The reaction (II)+(III)→(IV) can be carried out in an inert solvent orin the absence of a solvent. Inert solvents for the process step(II)+(III)→(IV) are, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol or tert-butanol, ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride,trichloroethylene or chlorobenzene, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane or mineral oil fractions, or othersolvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile or else water. It is also possible to use mixtures of thesolvents mentioned. Preference is given to dimethylformamide and tolueneand also to a mixture of dimethylformamide and toluene.

Suitable bases for the process step (II)+(III)→(IV) are alkali metalhydrides such as sodium hydride, alkali metal hydroxides such as, forexample, lithium hydroxide, sodium hydroxide or potassium hydroxide,alkali metal carbonates such as lithium carbonate, sodium carbonate,potassium carbonate or caesium carbonate, alkali metal bicarbonates suchas sodium bicarbonate or potassium bicarbonate, alkali metal alkoxidessuch as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, amides such as sodiumamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amideor potassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds such as butyllithium or phenyllithium, ororganic amines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to pyridine.

The reaction (II)+(III)→(IV) is generally carried out in a temperaturerange from −10° C. to +30° C., preferably at from 0° C. to +20° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

Inert solvents for the process step (IV)+(V)→(I) are, for example,alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, trichloroethylene or chlorobenzene, hydrocarbons such asbenzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions,or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide(DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile or else water. It is also possible to use mixtures of thesolvents mentioned. Preference is given to THF.

Suitable bases for the process step (IV)+(V)→(I) are alkali metalhydrides such as sodium hydride, alkali metal hydroxides such as, forexample, lithium hydroxide, sodium hydroxide or potassium hydroxide,alkali metal carbonates such as lithium carbonate, sodium carbonate,potassium carbonate or caesium carbonate, alkali metal bicarbonates suchas sodium bicarbonate or potassium bicarbonate, alkali metal alkoxidessuch as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, amides such as sodiumamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amideor potassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds such as butyllithium or phenyllithium, ororganic amines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to lithiumbis(trimethylsilyl)amide or sodium hydride.

The reaction (IV+(V)→(I) is generally carried out in a temperature rangefrom −10° C. to +30° C., preferably at from 0° C. to +20° C. Thereaction can be carried out at atmospheric, elevated or reduced pressure(for example from 0.5 to 5 bar). The reaction is generally carried outat atmospheric pressure.

The compounds of the formulae (III) and (V) are commercially available,known from the literature or can be prepared in analogy to literatureprocesses.

The preparation process described above is illustrated by way of exampleby the synthesis scheme below (Scheme 1):

The compound of the formula (II) can be prepared by reacting thecompound of the formula (VI)

in which R¹ and R⁶ each have the meanings given above,in an inert solvent in the presence of a suitable base with a compoundof the formula (VII)

in which R² has the meaning given above and

X² is a suitable leaving group, for example halogen, mesylate, tosylateor triflate, to give a compound of the formula (VIII)

in which R¹, R² and R⁶ each have the meanings given above,and then reducing this in an inert solvent with a suitable reducingagent to give a compound of the formula (II).

Inert solvents for the process step (VI)+(VII)→(VIII) are, for example,alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or mineral oilfractions, or other solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), dimethylacetamide,N-methylpyrrolidone (NMP), pyridine, acetonitrile, sulfolane or elsewater. It is also possible to use mixtures of the solvents mentioned.Preference is given to dioxane or DMF.

Suitable bases for the process step (VI)+(VII)→(VIII) are alkali metalhydrides such as sodium hydride, alkali metal hydroxides such as, forexample, lithium hydroxide, sodium hydroxide or potassium hydroxide,alkali metal carbonates such as lithium carbonate, sodium carbonate,potassium carbonate or caesium carbonate, alkali metal bicarbonates suchas sodium bicarbonate or potassium bicarbonate, alkali metal alkoxidessuch as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, amides such as sodiumamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amideor potassium bis(trimethylsilyl)amide or lithium diisopropylamide,organometallic compounds such as butyllithium or phenyllithium, ororganic amines such as triethylamine, diisopropylethylamine, pyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to lithiumbis(trimethylsilyl)amide or sodium hydride.

The reaction (VI)+(VII)→(VIII) is generally carried out in a temperaturerange of from 0° C. to +120° C., preferably at from +20° C. to +80° C.,if appropriate in a microwave. The reaction can be carried out atatmospheric, elevated or reduced pressure (for example from 0.5 to 5bar). The reaction is generally carried out at atmospheric pressure.

The reduction (VIII)→(II) is carried out in the presence of a suitablecatalyst in an inert solvent in a temperature range of from +20° C. to+40° C. under hydrogen standard pressure.

Inert solvents for the reduction (VIII)→(II) are, for example, alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, or othersolvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine,acetonitrile or else water. It is also possible to use mixtures of thesolvents mentioned. Preference is given to DMF and pyridine.

Suitable catalysts for the conversion (VIII)→(II) are, for example,palladium on activated carbon, platinum on carbon, palladium hydroxideor Raney nickel.

The reduction (VIII)→(II) can alternatively be effected with a metal ormetal salt, for example iron, zinc or tin(II) chloride in a suitableacid, for example hydrogen chloride/hydrochloric acid, sulfuric acid,phosphoric acid or acetic acid, within a temperature range of +20° C. to+140° C.

The compounds of the formula (VI) are known from the literature (see,for example, WO 2008/031513 example 4A), can be prepared analogously toprocesses known from the literature or can be prepared as described inthe experimental section (examples 3A to 6A).

The process described above is illustrated by way of example by thesynthesis scheme below (Scheme 2):

The compounds according to the invention act as potent stimulators ofsoluble guanylate cyclase, have useful pharmacological properties andare therefore suitable for treatment and/or prophylaxis of disorders inhumans and animals.

The compounds according to the invention cause vasorelaxation andinhibition of platelet aggregation, and lead to a decrease in bloodpressure and to a rise in coronary blood flow. These effects aremediated by direct stimulation of soluble guanylate cyclase and anintracellular rise in cGMP. In addition, the inventive compounds enhancethe action of substances which increase the cGMP level, for example EDRF(endothelium-derived relaxing factor), NO donors, protoporphyrin IX,arachidonic acid or phenylhydrazine derivatives.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prophylaxis of cardiovasculardisorders such as, for example, hypertension, acute and chronic heartfailure, coronary heart disease, stable and unstable angina pectoris,peripheral and cardiac vascular disorders, arrhythmias, atrial andventricular arrhythmias and impaired conduction such as, for example,atrioventricular blocks degrees I-III (AB block I-III), supraventriculartachyarrhythmia, atrial fibrillation, atrial flutter, ventricularfibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsadede pointes tachycardia, atrial and ventricular extrasystoles,AV-junctional extrasystoles, Sick-Sinus syndrome, syncopes, AV-nodalre-entry tachycardia, Wolff-Parkinson-White syndrome, of acute coronarysyndrome (ACS), autoimmune cardiac disorders (pericarditis,endocarditis, valvolitis, aortitis, cardiomyopathies), cardiogenicshock, aneurysms, boxer cardiomyopathy (premature ventricularcontraction (PVC)), for the treatment and/or prophylaxis ofthromboembolic disorders and ischaemias such as myocardial ischaemia,myocardial infarction, stroke, shock, cardiac hypertrophy, transient andischaemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, oedemaformation such as, for example, pulmonary oedema, cerebral oedema, renaloedema or oedema caused by heart failure, peripheral circulatorydisturbances, reperfusion damage, arterial and venous thromboses,microalbuminuria, myocardial insufficiency, endothelial dysfunction, toprevent restenoses, for example after thrombolysis therapies,percutaneous transluminal angioplasties (PTA), transluminal coronaryangioplasties (PTCA), heart transplants and bypass operations, and alsomicro- and macrovascular damage (vasculitis), increased levels offibrinogen and of low-density lipoprotein (LDL) and increasedconcentrations of plasminogen activator inhibitor 1 (PAI-1), and alsofor the treatment and/or prophylaxis of erectile dysfunction and femalesexual dysfunction.

In the context of the present invention, the term heart failure alsoincludes more specific or related types of disease, such as acutedecompensated heart failure, right heart failure, left heart failure,global failure, ischemic cardiomyopathy, dilated cardiomyopathy,hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heartdefects, heart valve defects, heart failure associated with heart valvedefects, mitral stenosis, mitral insufficiency, aortic stenosis, aorticinsufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonaryvalve stenosis, pulmonary valve insufficiency, combined heart valvedefects, myocardial inflammation (myocarditis), chronic myocarditis,acute myocarditis, viral myocarditis, diabetic heart failure, alcoholiccardiomyopathy, cardiac storage disorders, and diastolic and systolicheart failure.

In addition, the compounds according to the invention can also be usedfor the treatment and/or prophylaxis of arteriosclerosis, impaired lipidmetabolism, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias,hyperlipidemias, hypercholesterolemias, abetalipoproteinemias,sitosterolemia, xanthomatosis, Tangier disease, adiposity, obesity andof combined hyperlipidemias and metabolic syndrome.

Moreover, the compounds according to the invention can be used fortreatment and/or prophylaxis of primary and secondary Raynaud'sphenomenon, of microcirculation disorders, claudication, peripheral andautonomic neuropathies, diabetic microangiopathies, diabeticretinopathy, diabetic ulcers at the extremities, gangrene, CRESTsyndrome, erythematosis, onychomycosis, rheumatic disorders, and forpromotion of wound healing.

The compounds according to the invention are furthermore suitable fortreating urological disorders such as, for example, benign prostatesyndrome (BPS), benign prostate hyperplasia (BPH), benign prostateenlargement (BPE), bladder outlet obstruction (BOO), lower urinary tractsyndromes (LUTS, including Feline Urological Syndrome (FUS)), disordersof the urogenital system including neurogenic over-active bladder (OAB)and (IC), incontinence (UI) such as, for example, mixed urinaryincontinence, urge urinary incontinence, stress urinary incontinence oroverflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benignand malignant disorders of the organs of the male and femal urogenitalsystem.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of kidney disorders, in particular ofacute and chronic renal insufficiency and acute and chronic renalfailure. In the context of the present invention, the term renalinsufficiency comprises both acute and chronic manifestations thereof,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, glomerulonephritis, acute glomerulonephritis,glomerulosclerosis, tubulointerstitial diseases, nephropathic diseasessuch as primary and congenital kidney disease, nephritis, immunologicalkidney diseases such as kidney graft rejection and immunocomplex-inducedkidney diseases, nephropathy induced by toxic substances, nephropathyinduced by contrast agents, diabetic and non-diabetic nephropathy,pyelonephritis, renal cysts, nephrosclerosis, hypertensivenephrosclerosis and nephrotic syndrome, which can be characterizeddiagnostically for example by abnormally reduced creatinine and/or waterexcretion, abnormally raised blood concentrations of urea, nitrogen,potassium and/or creatinine, altered activity of renal enzymes such as,for example, glutamyl synthetase, altered urine osmolarity or urinevolume, increased microalbuminurea, macroalbuminurea, lesions onglomerulae and arterioles, tubular dilatation, hyperphosphatemia and/orneed for dialysis. The present invention also comprises the use of thecompounds according to the invention for the treatment and/orprophylaxis of sequelae of renal insufficiency, for example pulmonaryedema, heart failure, uremia, anemia, electrolyte disturbances (forexample hypercalemia, hyponatremia) and disturbances in bone andcarbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitablefor the treatment and/or prophylaxis of asthmatic disorders, pulmonaryarterial hypertension (PAH) and other forms of pulmonary hypertension(PH), chronic-obstructive pulmonary disease (COPD), acute respiratorydistress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsindeficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for examplepulmonary emphysema induced by cigarette smoke) and cystic fibrosis(CF).

The compounds described in the present invention also represent activecompounds for controlling central nervous system diseases characterizedby disturbances of the NO/cGMP system. More particularly, they aresuitable for improving perception, concentration, learning or memoryafter cognitive impairments such as those occurring particularly in theevent of situations/diseases/syndromes such as mild cognitiveimpairment, age-associated learning and memory impairments,age-associated memory losses, vascular dementia, craniocerebral trauma,stroke, dementia occuring after strokes (post-stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children having learning and memoryproblems, Alzheimer's disease, Lewy body dementia, dementia withdegeneration of the frontal lobes including Pick's syndrome, Parkinson'sdisease, progressive nuclear palsy, dementia with corticobasaldegeneration, amyolateral sclerosis (ALS), Huntington's disease,demyelination, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia orKorsakoff's psychosis. They are also suitable for treatment and/orprophylaxis of central nervous system disorders such as states ofanxiety, tension and depression, CNS-related sexual dysfunction anddisrupted sleep, and for control of pathological disturbances of theintake of food, stimulants and addictive substances.

Furthermore, the compounds according to the invention are also suitablefor regulating cerebral blood flow and are thus effective agents forcontrol of migraine. They are also suitable for prophylaxis and controlof sequelae of cerebral infarct (cerebral apoplexy) such as stroke,cerebral ischemia and skull-brain trauma. The compounds according to theinvention can likewise be employed for controlling states of pain andtinnitus.

In addition, the compounds according to the invention haveantiinflammatory action and can therefore be used as antiinflammatoryagents for the treatment and/or prophylaxis of sepsis (SIRS), multipleorgan failure (MODS, MOF), inflammatory disorders of the kidney, chronicintestinal inflammations (IBD, Crohn's disease, UC), pancreatitis,peritonitis, rheumatoid disorders, inflammatory skin diseases andinflammatory eye diseases.

Furthermore, the compounds according to the invention can also be usedfor the treatment and/or prophylaxis of autoimmune diseases.

The compounds according to the invention are furthermore suitable forthe treatment and/or prophylaxis of fibrotic disorders of the internalorgans such as, for example, the lung, the heart, the kidney, the bonemarrow and in particular the liver, and also dermatological fibroses andfibrotic eye disorders. In the context of the present invention, theterm fibrotic disorders includes in particular the following terms:hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitialrenal fibrosis, fibrotic damage resulting from diabetes, bone marrowfibrosis and similar fibrotic disorders, scleroderma, morphea, keloids,hypertrophic scarring (also following surgical procedures), naevi,diabetic retinopathy and proliferative vitroretinopathy.

The compounds according to the invention are furthermore suitable forcontrolling postoperative scarring, for example as a result of glaucomaoperations.

The compounds according to the invention can also be used cosmeticallyfor ageing and keratinized skin.

Moreover, the compounds according to the invention are suitable for thetreatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis,glaucoma and gastroparesis.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

The present invention further provides the compounds according to theinvention for use in a method for the treatment and/or prophylaxis ofheart failure, angina pectoris, hypertension, pulmonary hypertension,ischaemias, vascular disorders, thromboembolic disorders andarteriosclerosis.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for treatmentand/or prophylaxis of disorders, in particular the disorders mentionedabove.

The present invention further provides a method for treatment and/orprophylaxis of disorders, in particular the disorders mentioned above,using an effective amount of at least one of the compounds according tothe invention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active compounds. The presentinvention further provides medicaments comprising at least one of thecompounds according to the invention and one or more further activecompounds, especially for the treatment and/or prophylaxis of theaforementioned disorders. Preferred examples of suitable active compoundcombinations include:

-   -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerine, isosorbide mononitrate,        isosorbide dinitrate, molsidomine or SIN1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), for example inhibitors of        phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   antithrombotic agents, by way of example and with preference        from the group of the platelet aggregation inhibitors, the        anticoagulants or the profibrinolytic substances;    -   hypotensive active compounds, by way of example and with        preference from the group of the calcium antagonists,        angiotensin All antagonists, ACE inhibitors, endothelin        antagonists, renin inhibitors, alpha-receptor blockers,        beta-receptor blockers, mineralocorticoid receptor antagonists,        and the diuretics; and/or    -   active compounds which modify lipid metabolism, by way of        example and with preference from the group of the thyroid        receptor agonists, cholesterol synthesis inhibitors, by way of        example and with preference HMG-CoA reductase inhibitors or        squalene synthesis inhibitors, the ACAT inhibitors, CETP        inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or        PPAR-delta agonists, cholesterol absorption inhibitors, lipase        inhibitors, polymeric bile acid adsorbents, bile acid        reabsorption inhibitors and lipoprotein (a) antagonists.

Antithrombotic agents are preferably understood to mean compounds fromthe group of the platelet aggregation inhibitors, the anticoagulants orthe profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor such as, by way of example and with preferenceaspirin, clopidogrel, ticlopidin or dipyridamol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitorsuch as, by way of example and with preference ximelagatran, dabigatran,melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, by way of example and with preference tirofiban orabciximab.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a factor Xa inhibitor, by way ofexample and with preference rivaroxaban (BAY 59-7939), DU176b, apixaban,otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112,YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with heparin or with a low molecular weight(LMW) heparin derivative.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a vitamin K antagonist, by way ofexample and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from thegroup of calcium antagonists, angiotensin All antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,by way of example and with preference nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an alpha-1-receptor blocker, by way ofexample and with preference prazosin.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a beta-receptor blocker, by way ofexample and with preference propranolol, atenolol, timolol, pindolol,alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol,mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol,bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol,landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin Allantagonist, by way of example and with preference losartan, candesartan,valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, byway of example and with preference enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an endothelin antagonist, by way ofexample and with preference bosentan, darusentan, ambrisentan orsitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor, byway of example and with preference aliskiren, SPP600 or SPP800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, by way of example and with preferencespironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, by way ofexample and with preference furosemide.

Lipid metabolism modifiers are preferably understood to mean compoundsfrom the group of the CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbents, bile acidreabsorption inhibitors, lipase inhibitors and the lipoprotein (a)antagonists.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a CETP inhibitor, by way of example andwith preference dalcetrapib, BAY 60-5521, anacetrapib oder CETP vaccine(CETi-1).

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a thyroid receptor agonist, by way ofexample and with preference D-thyroxine, 3,5,3′-triiodothyronine (T3),CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an HMG-CoA reductase inhibitor from theclass of statins, by way of example and with preference lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin orpitavastatin.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a squalene synthesis inhibitor, by wayof example and with preference BMS188494 or TAK475.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an ACAT inhibitor, by way of exampleand with preference avasimibe, melinamide, pactimibe, eflucimibe orSMP797.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with an MTP inhibitor, by way of example andwith preference implitapide, BMS201038, R103757 or JTT130.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a PPAR-gamma agonist, by way of exampleand with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,by way of example and with preference GW 501516 or BAY 685042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, by way of example and with preference ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a lipase inhibitor, by way of exampleand with preference orlistat.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a polymeric bile acid adsorbent, by wayof example and with preference cholestyramine, colestipol, colesolvam,CholestaGel or colestimide.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a bile acid reabsorption inhibitor, byway of example and with preference ASBT (=IBAT) inhibitors, for exampleAZD7806, S8921, AK105, BARI1741, SC435 or SC635.

In a preferred embodiment of the invention, the inventive compounds areadministered in combination with a lipoprotein (a) antagonist, by way ofexample and with preference gemcabene calcium (CI1027) or nicotinicacid.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, nontoxic, pharmaceutically suitable auxiliaries, andfor the use thereof for the aforementioned purposes.

The compounds according to the invention may act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art, which release the compounds accordingto the invention rapidly and/or in a modified manner and which containthe compounds according to the invention in crystalline and/oramorphized and/or dissolved form, for example tablets (uncoated orcoated tablets, for example with gastric juice-resistant orretarded-dissolution or insoluble coatings which control the release ofthe inventive compound), tablets or films/oblates which disintegraterapidly in the oral cavity, films/lyophilizates or capsules (for examplehard or soft gelatin capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished with avoidance of anabsorption step (for example by an intravenous, intraarterial,intracardiac, intraspinal or intralumbar route) or with inclusion of anabsorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Suitableadministration forms for parenteral administration include injection andinfusion formulations in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/oblates or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Preference is given to oral or parenteral administration, especiallyoral administration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be accomplished in a mannerknown per se by mixing with inert nontoxic pharmaceutically suitableauxiliaries. These auxiliaries include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulfate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), dyes (e.g. inorganic pigments, for example iron oxides) andflavor and/or odor correctors.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration, the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, specifically as a function of the body weight, route ofadministration, individual response to the active compound, nature ofthe preparation and time or interval over which administration takesplace. For instance, in some cases, less than the aforementioned minimumamount may be sufficient, while in other cases the upper limit mentionedmust be exceeded. In the case of administration of greater amounts, itmay be advisable to divide them into several individual doses over theday.

The working examples which follow illustrate the invention. Theinvention is not limited to the examples.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration figures forliquid/liquid solutions are each based on volume.

A. EXAMPLES Abbreviations and Acronyms

aq. aqueous solution

calc. calculated

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

eq. equivalent(s)

ESI electrospray ionization (in MS)

Et ethyl

h hour(s)

HPLC high-pressure high-performance liquid chromatography

HRMS high-resolution mass spectrometry

conc. concentrated

LC/MS liquid chromatography-coupled mass spectroscopy

LiHMDS lithium hexamethyldisilazide

Me methyl

min minute(s)

MS mass spectrometry

MTBE methyl tert-butyl ether

NMR nuclear magnetic resonance spectroscopy

Pd₂dba₃ tris(dibenzylideneacetone)dipalladium

Ph phenyl

RP reversed phase

RT room temperature

R_(t) retention time (in HPLC)

THF tetrahydrofuran

UV ultraviolet spectrometry

v/v ratio by volume (of a solution)

XPHOS dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine

LC/MS Methods:

Method 1 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210-400 nm.

Method 2 (LC-MS):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3μ, 20 mm×4 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100%A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A (flow rate 2.5ml/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UVdetection: 210 nm

Method 3 (LC-MS):

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: ZorbaxSB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025%formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid;gradient: 0.0 min 98% A-0.9 min 25% A-1.0 min 5% A-1.4 min 5% A-1.41 min98% A-1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UVdetection: DAD, 210 nm.

Method 4 (LC-MS):

MS instrument: Waters; HPLC instrument: Waters (column Waters X-BridgeC18, 18 mm×50 mm, 5 μm, mobile phase A: water+0.05% triethylamine,mobile phase B: acetonitrile (ULC)+0.05% triethylamine; gradient: 0.0min 95% A-0.15 min 95% A-8.0 min 5% A-9.0 min 5% A; flow rate: 40ml/min; UV detection: DAD; 210-400 nm).

Method 5 (LC-MS):

MS instrument: Waters; HPLC instrument: Waters (column Phenomenex Luna5μ C18(2) 100A, AXIA Tech. 50×21.2 mm, mobile phase A: water+0.05%formic acid, mobile phase B: acetonitrile (ULC)+0.05% formic acid;gradient: 0.0 min 95% A-0.15 min 95% A-8.0 min 5% A-9.0 min 5% A; flowrate: 40 ml/min; UV detection: DAD; 210-400 nm).

Starting Materials and Intermediates:

Example 1A2-[3-(2-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine

The synthesis of this compound is described in WO 2008/031513, example8.

Example 2A Methyl{4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The synthesis of this compound is described in WO 2008/031513, example9.

Example 3A 3,5-Difluoropyridine-2-carbonyl chloride

A suspension of 5.00 g (31.4 mmol) of 3,5-difluoropyridine-2-carboxylicacid in thionyl chloride (21 ml) was heated to reflux for 5 h. Thesolution was concentrated, and the residue was twice taken up in alittle toluene and concentrated again. This gave 3.80 g of a solid,which was reacted further directly without further purification.

Example 4A Methyl3-(3,5-difluoropyridin-2-yl)-2-(2-fluorophenyl)-3-oxopropanoate

21.4 ml (21.4 mmol) of lithium hexamethyldisilazide (1.0 M in THF) wereinitially charged in THF (30 ml) under argon and a solution of 3.00 g(17.8 mmol) of methyl 2-fluorophenylacetate in THF (15 ml) was addeddropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h,and then a solution of 3.80 g (21.4 mmol) of the compound from example3A in THF (15 ml) was added dropwise. The solution was stirred at −78°C. for 1 h, then brought to RT, and saturated aqueous ammonium chloridesolution was added in portions. The mixture was diluted with water andextracted twice with ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered and concentrated. The residue wasstirred with MTBE, the solid was filtered off and the filtrate wasconcentrated. Silica gel chromatography (mobile phase:cyclohexane-ethylacetate: 30:1, 20:1) of the residue gave 3.66 g (87% pure, 57% oftheory) of the title compound. The crude product was reacted withoutfurther purification.

LC-MS (method 1): R_(t)=1.05 min; MS (ESIpos): m/z=310 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.66 (s, 3H), 6.25 (s, 1H), 7.20-7.28 (m,4H), 7.31-7.38 (m, 1H), 8.15-8.23 (m, 1H), 8.68-8.71 (m, 1H).

Example 5A 1-(3,5-Difluoropyridin-2-yl)-2-(2-fluorophenyl)ethanone

11.65 g (37.67 mmol) of the compound from example 4A were initiallycharged in DMSO (37 ml). Subsequently, 2.42 g (41.44 mmol) of sodiumchloride and water (7 ml) were added, and the mixture was stirred in amicrowave at 150° C. for 30 min. The reaction mixture was diluted withethyl acetate, and the organic phase was washed three times with waterand once with saturated aqueous sodium chloride solution, dried oversodium sulfate, filtered and concentrated. This gave 9.07 g (89% pure,85% of theory) of the desired compound as a solid, which was reactedwithout further purification.

LC-MS (method 1): R_(t)=1.05 min; MS (ESIpos): m/z=252 (M+H)⁺.

¹H NMR (400 MHz, DMSO-d₆): δ=4.53 (s, 2H), 7.15-7.22 (m, 2H), 7.30-7.37(m, 2H), 8.11-8.18 (m, 1H), 8.70-8.72 (m, 1H).

Example 6A 6-Fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine

9.07 g (32.4 mmol) of the compound from example 5A were initiallycharged in pyridine (84 ml). Subsequently, 8.10 g (162 mmol) ofhydrazine hydrate and 19.8 mg (0.162 mmol) of 4-dimethylaminopyridinewere added, and the mixture was heated at reflux for 30 min. Thereaction mixture was diluted with ethyl acetate at RT and washed fourtimes with 10% strength aqueous citric acid solution. The organic phasewas subsequently washed with saturated aqueous sodium chloride solution,dried over sodium sulfate, filtered and concentrated. MTBE was added tothe residue and the solids were filtered off. The latter were driedunder high vacuum and gave 1.79 g (79% pure, 18% of theory) of the titlecompound. The filtrate was concentrated and gave a further 4.86 g (61%pure, 37% of theory) of the title compound. The two fractions werecombined and reacted without further purification.

LC-MS (method 2): R_(t)=1.87 min; MS (ESIpos): m/z=246 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=4.33 (s, 2H), 7.06-7.12 (m, 1H), 7.12-7.19(m, 1H), 7.22-7.29 (m, 1H), 7.29-7.35 (m, 1H), 7.87 (dd, 1H), 7.84-7.89(m, 1H), 8.48-8.51 (br. s, 1H).

Example 7A2-[6-Fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-5-nitropyrimidine-4,6-diamine

156 mg (about 66% pure, 0.636 mmol) of the compound from example 6A weredissolved in DMF (3.5 ml), 28 mg (0.70 mmol) of sodium hydride (60% inmineral oil) were then added and the mixture was stirred at RT for 2 h.115 mg (0.604 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine(synthesis: Helvetica Chimica Acta (1951), 34, 835-40) were then added,and the reaction mixture was stirred at 80° C. for another 1 h. Aftercooling to RT, the mixture was added to water. The suspension obtainedin this manner was filtered off and the solid was washed repeatedly withwater and then dried under high vacuum. This gave 196 mg (77% of theory)of the title compound in solid form.

LC-MS (method 2): R_(t)=2.13 min; MS (ESIpos): m/z=399 (M+H)+

Example 8A2-[6-Fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5,6-triamine

196 mg (0.492 mmol) of the compound from example 7A were initiallycharged in pyridine (22 ml), 74 mg of palladium on carbon (10% byweight) were then added and the mixture was hydrogenated at standardhydrogen pressure overnight. The reaction mixture was then filteredthrough kieselguhr, the filter cake was washed with ethanol and thefiltrate was concentrated. The residue was triturated with ethanol at50° C., and the solid was filtered off and dried under high vacuum. Thisgave 107 mg (58% of theory) of the title compound.

LC-MS (method 1): R_(t)=0.85 min; MS (ESIpos): m/z=369 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆): δ=3.76 (s, 2H), 4.39 (s, 2H), 6.12 (s, 4H),7.07-7.14 (m, 1H), 7.14-7.21 (m, 1H), 7.23-7.31 (m, 1H), 7.31-7.37 (m,1H), 8.58-8.62 (m, 1H), 8.94 (dd, 1H).

Example 9A Methyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

Under argon, 1.00 g (2.72 mmol) of the compound from example 8A wasinitially charged in pyridine (55 ml), the mixture was cooled to 0° C.and 228 μl (2.72 mmol) of methyl chloroformate (solution in 10 ml ofdichloromethane) were then added dropwise. The reaction mixture wasstirred further at RT overnight and then concentrated. The residue wastriturated with ethanol and the solid was filtered off and dried at 50°C. under high vacuum. This gave 873 mg (75% of theory) of the targetcompound as a solid. The filtrate was re-concentrated, and preparativeRP-HPLC (acetonitrile:water (+0.1% formic acid) gradient) of the residuegave a further 180 mg (16% of theory) of the target compound.

LC-MS (method 1): R_(t)=0.88 min; MS (ESIpos): m/z=427 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=3.48-3.67 (m, 3H),4.40 (s, 2H), 6.45 (br. s, 4H), 7.08-7.14 (m, 1H), 7.15-7.21 (m, 1H),7.24-7.31 (m, 1H), 7.31-7.37 (m, 1H), 7.60 (br. s, 0.2H), 7.90 (br. s,0.8H), 8.61-8.65 (m, 1H), 9.04 (dd, 1H).

Example 10A 3-(2-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridine

The synthesis of this compound is described in WO 2008/031513, example4A.

Example 11A2-[3-(2-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]-5-nitropyrimidine-4-amine

795 mg (3.50 mmol) of the compound from Example 10A were initiallycharged in DMF (19 ml), 154 mg (3.85 mmol) of sodium hydride (60% inmineral oil) were then added and the mixture was stirred at RT for 1 h.580 mg (3.32 mmol) of 2-chloro-5-nitropyrimidine-4-amine (J. Med. Chem.(1992), 35, 4455-4463) were then added, and the reaction mixture wasstirred at 80° C. for another 2 h. The mixture was brought to RT andthen added to water. The suspension obtained in this manner was filteredoff and the solid was washed repeatedly with water and then dried underhigh vacuum. This gave 281 mg of the desired compound. The motherliquor, which still contained product, was extracted three times withethyl acetate. The combined organic phases were dried over sodiumsulfate, filtered and concentrated on a rotary evaporator. This gave afurther 512 mg of the target compound. The crude product obtained inthis manner was reacted without further purification.

LC-MS (method 1): R_(t)=1.01 min; MS (EIpos): m/z=366 [M+H]⁺.

Example 12A2-[3-(2-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidine-4,5-diamine

793 mg (217 mmol) of the compound from example 11A were initiallycharged in pyridine (97 ml), 328 mg of palladium on carbon (10% byweight) were then added and the mixture was hydrogenated at standardhydrogen pressure overnight. The reaction mixture was then filteredthrough kieselguhr, the filter cake was washed with ethanol and thefiltrate was concentrated. The residue was chromatographed on silica gel(dichloromethane:methanol 30:1→20:1) and the product fractions wereconcentrated. This gave 330 mg (83% pure) of the desired compound. Thecrude product was reacted without further purification.

LC-MS (method 1): R_(t)=0.75 min; MS (EIpos): m/z=336 (M+H)⁺.

Example 13A Isopropyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

300 mg (0.81 mmol) of the compound from example 8A were initiallycharged in 10 ml of pyridine, and the mixture was cooled to 0° C. 0.81ml (0.81 mmol) of isopropyl chloroformate was then added dropwise, andthe mixture was stirred at 0° C. for a further 60 min. The reactionmixture was brought to RT and purified directly by means of preparativeRP-HPLC (acetonitrile:water (+0.1% formic acid) gradient). This gave 88mg of the target compound (24% of theory).

LC-MS (method 1): R_(t)=0.97 min; MS (EIpos): m/z=455 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=1.06-1.31 (m, 6H),4.40 (s, 2H), 4.77-4.85 (m, 1H), 6.39 (br. s, 4H), 7.08-7.14 (m, 1H),7.15-7.21 (m, 1H), 7.24-7.31 (m, 1H), 7.31-7.38 (m, 1H), 7.43-7.52 (m,0.25H), 7.78-7.86 (m, 0.75H), 8.61-8.65 (m, 1H), 9.01-9.09 (m, 1H).

Example 14A Ethyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The compound was prepared analogously to example 13A using ethylchloroformate. This gave 77 mg of the target compound (21% of theory).

LC-MS (method 1): R_(t)=0.92 min; MS (EIpos): m/z=441 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=1.06-1.29 (m, 3H),3.98-4.11 (m, 2H), 4.40 (s, 2H), 6.44 (br. s, 4H), 7.07-7.14 (m, 1H),7.15-7.21 (m, 1H), 7.24-7.31 (m, 1H), 7.31-7.37 (m, 1H), 7.54 (br. s,0.25H), 7.88 (br. s, 0.75H), 8.61-8.65 (m, 1H), 9.02-9.08 (m, 1H).

Example 15A Methyl{4-amino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

Under argon, 330 mg (0.98 mmol) of the compound from example 12A wereinitially charged in pyridine (12 ml), the mixture was cooled to 0° C.and 84 μl (108 mmol) of methyl chloroformate were then added dropwise.The reaction mixture was stirred further at RT overnight, and ethylacetate was then added. The organic phase was washed twice withsaturated aqueous sodium bicarbonate solution, dried over magnesiumsulfate, filtered and concentrated. The residue was separated bypreparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient),giving 241 mg (62% of theory) of the target compound as a colorlesssolid.

LC-MS (method 1): R_(t)=0.85 min; MS (EIpos): m/z=394 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=3.67 (s, 3H), 4.44 (s, 2H), 7.07-7.14(m, 1H), 7.15-7.22 (m, 1H), 7.23-7.41 (m, 3H), 7.51-7.58 (m, 1H), 8.24(br. s, 1H), 8.61-8.66 (m, 1H), 8.75 (br. s, 1H), 8.98-9.08 (m, 1H).

WORKING EXAMPLES Example 1 Methyl{4-amino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}(2-fluorobenzyl)carbamate

47 mg (0.12 mmol) of the compound from example 15A were initiallycharged in 3 ml of THF, and the mixture was cooled to 0° C.Subsequently, 5 mg (0.12 mmol) of sodium hydride (60% in mineral oil)were added and the mixture was stirred at 0° C. for a further 30 min.Thereafter, 14 μl (0.12 mmol) of 2-fluorobenzyl bromide were addeddropwise, and the mixture was stirred at RT overnight. The reactionmixture was diluted with ethyl acetate and the organic phase was washedtwice with saturated aqueous sodium bicarbonate solution. The organicphase was then dried over magnesium sulfate, filtered and concentrated.The residue was purified by means of preparative HPLC(acetonitrile:water (+0.1% formic acid) gradient). The crude productobtained in this manner was purified by means of preparative thin-layerchromatography (mobile phase: dichloromethane-methanol 20:1). This gave8 mg of the target compound (13% of theory).

LC-MS (method 1): R_(t)=1.10 min; MS (EIpos): m/z=502 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): 6 [ppm]=3.56-3.79 (m, 3H),4.31-4.39 (m, 1H), 4.42 (s, 2H), 5.06-5.16 (m, 1H), 7.07-7.21 (m, 4H),7.23-7.39 (m, 3H), 7.43-7.50 (m, 1H), 7.53 (dd, 1H), 7.56-7.74 (m, 2H),7.64-7.70 (m, 1H), 8.60-8.65 (m, 1H), 8.97-9.02 (m, 1H).

Example 2 Methyl{4-amino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin−1-yl]pyrimidin-5-yl}benzylcarbamate

The compound was prepared analogously to example 1 using benzyl bromide.This gave 7 mg of the target compound (13% of theory).

LC-MS (method 1): R_(t)=1.11 min; MS (EIpos): m/z=484 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): 6 [ppm]=3.57-3.81 (m, 3H),4.12-4.21 (m, 1H), 4.41 (s, 1H), 5.06-5.15 (m, 1H), 7.07-7.13 (m, 1H),7.14-7.21 (m, 1H), 7.23-7.38 (m, 7H), 7.52 (dd, 1H), 7.55-7.66 (m, 2H),7.57-7.63 (m, 1H), 8.60-8.64 (m, 1H), 8.96-9.00 (m, 1H).

Example 3 Methyl{4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}(2-fluorobenzyl)carbamate

The compound was prepared in analogy to example 1 from 89 mg (0.22 mmol)of the compound in example 2A. Purification was carried out by means ofpreparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient).This gave 80 mg of the target compound (67% of theory).

LC-MS (method 1): R_(t)=1.01 min; MS (EIpos): m/z=517 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): 6 [ppm]=3.57-3.79 (m, 3H),4.40 (s, 2H), 4.65-4.73 (m, 2H), 6.34 (br. s, 4H), 7.03-7.21 (m, 4H),7.22-7.36 (m, 3H), 7.44-7.50 (m, 1H), 7.51-7.59 (m, 1H), 8.56-8.62 (m,1H), 9.09-9.16 (m, 1H).

Example 4 Methyl{4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}(4-fluorobenzyl)carbamate

The compound was prepared in analogy to example 1 from 100 mg (0.245mmol) of the compound in example 2A and 31 μl (0.25 mmol) of4-fluorobenzyl bromide. Purification was carried out by means ofpreparative RP-HPLC (acetonitrile:water (+0.1% formic acid) gradient).This gave 92 mg of the target compound (72% of theory).

LC-MS (method 1): R_(t)=1.03 min; MS (EIpos): m/z=517 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): 6 [ppm]=3.60 (s, 2H), 3.75(s, 1H), 4.36-4.42 (m, 2H), 4.54-4.62 (m, 2H), 6.34 (br. s, 4H),7.00-7.12 (m, 3H), 7.14-7.21 (m, 1H), 7.22-7.36 (m, 2H), 7.36-7.44 (m,2H), 7.44-7.50 (m, 1H), 8.55-8.61 (m, 1H), 9.07-9.14 (m, 1H).

Example 5 Methylbenzyl{4,6-diamino-2-[3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The compound was prepared in analogy to example 1 from 100 mg (0.245mmol) of the compound in example 2A and 29 μl (0.25 mmol) of benzylbromide. Purification was carried out by means of preparative RP-HPLC(acetonitrile:water (+0.1% formic acid) gradient). This gave 79 mg ofthe target compound (63% of theory).

LC-MS (method 1): R_(t)=1.01 min; MS (EIpos): m/z=499 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=3.60 (s, 2H), 3.76(s, 1H), 4.39 (s, 2H), 4.55-4.63 (m, 2H), 6.30 (br. s., 3H), 7.05-7.12(m, 1H), 7.24 (br. s, 8H), 7.43-7.50 (m, 1H), 8.55-8.60 (m, 1H),9.07-9.14 (m, 1H).

Example 6 Isopropylbenzyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The compound was prepared in analogy to example 1 from 108 mg (0.238mmol) of the compound in example 13A and 29 μl (0.24 mmol) of benzylbromide. Purification was carried out by means of preparative RP-HPLC(acetonitrile:water (+0.1% formic acid) gradient). This gave 67 mg ofthe target compound (52% of theory).

LC-MS (method 1): R_(t)=1.01 min; MS (EIpos): m/z=545 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=1.07-1.18 (m, 4H),1.27-1.36 (m, 2H), 4.38 (s, 2H), 4.51-4.62 (m, 2H), 4.83-4.92 (m, 1H),6.29 (br. s, 4H), 7.06-7.13 (m, 1H), 7.14-7.21 (m, 1H), 7.21-7.40 (m,7H), 8.60-8.64 (m, 1H), 8.98-9.04 (m, 1H).

Example 7 Ethylbenzyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The compound was prepared in analogy to example 1 from 61 mg (0.14 mmol)of the compound in example 14A and 17 μl (0.14 mmol) of benzyl bromide.Purification was carried out by means of preparative RP-HPLC(acetonitrile:water (+0.1% formic acid) gradient). This gave 17 mg ofthe target compound (22% of theory).

LC-MS (method 1): R_(t)=1.13 min; MS (EIpos): m/z=531 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=1.11 (t, 2H),1.28-1.37 (m, 1H), 4.08 (q, 1.5H), 4.13-4.23 (m, 0.5H), 4.38 (s, 2H),4.54-4.62 (m, 2H), 6.35 (br. s, 4H), 7.07-7.12 (m, 1H), 7.14-7.20 (m,1H), 7.21-7.40 (m, 7H), 8.60-8.63 (m, 1H), 8.97-9.02 (m, 1H).

Example 8 Methylbenzyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate

The compound was prepared in analogy to example 1 from 86 mg (0.13 mmol)of the compound in example 9A and 16 μl (0.13 mmol) of benzyl bromide.Purification was carried out by means of preparative RP-HPLC(acetonitrile:water (+0.1% formic acid) gradient). This gave 50 mg ofthe target compound (73% of theory).

LC-MS (method 1): R_(t)=1.09 min; MS (EIpos): m/z=516 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆, rotamer mixture): δ [ppm]=3.60 (s, 2H), 3.76(s, 1H), 4.37 (s, 2H), 4.55-4.63 (m, 2H), 6.39 (br. s, 4H), 7.06-7.13(m, 1H), 7.14-7.20 (m, 1H), 7.21-7.40 (m, 7H), 8.59-8.64 (m, 1H),8.95-9.02 (m, 1H).

Example 9 Methyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}{2-[(phenylsulfonyl)methyl]benzyl}carbamate

39 mg (0.12 mmol) of 1-(bromomethyl)-2-[(phenylsulfonyl)methyl]benzenewere initially charged in a well of a 96 deep well multititer plate, anda solution of 426 mg (0.1 mmol) ofmethyl{4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamatein 0.6 ml of DMF were added. 130 mg (0.4 mmol) of cesium carbonate wereadded to this mixture. The multititer plate was covered and shaken at60° C. overnight. The mixture was then filtered off and the filtrate waspurified directly by preparative LC-MS (method 4 or 5). Theproduct-containing fractions were concentrated under reduced pressureusing a centrifugal drier. The residues of the individual fractions werein each case dissolved in 0.6 ml of DMSO and combined. The solvent wasthen evaporated completely in a centrifugal drier. This gave 17.3 mg(26% of theory) of the target product.

LC-MS (method 3): R_(t)=1.21 min; MS (ESIpos): m/z=671 (M+H)⁺.

The following compounds in table 1 were prepared analogously to example9.

TABLE 1 Ex. No Structure IUPAC name Yield Analytical data 10

methyl (2- chlorobenzyl){4,6-diamino- 2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate  17 mg,  30% of theory LC-MS (method 3): R_(t) = 1.20 min. MS (ESIpos):m/z = 551 (M + H)⁺ 11

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[3-(trifluoromethyl)benzyl] carbamate 17.4 mg  30% of theory LC-MS (method3): R_(t) = 1.22 min. MS (ESIpos): m/z = 585 (M + H)⁺ 12

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[(4- fluoro-1-naphthyl)methyl]carbamate   20 mg  34% of theory LC-MS (method 3): R_(t)= 1.24 min. MS (ESIpos): m/z = 585 (M + H)⁺ 13

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(quinolin-2-ylmethyl)carbamate  5.2 mg  8% of theory LC-MS (method 3): R_(t) = 1.21min. MS (ESIpos): m/z = 568 (M + H)⁺ purity: 90% 14

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2-fluorobenzyl)carbamate 18.9 mg  32% of theory LC-MS (method 3): R_(t) =1.17 min. MS (ESIpos): m/z = 535 (M + H)⁺ purity: 91% 15

methyl 2-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}-3-nitrobenzoate 15.9 mg  24% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 620 (M + H)⁺ purity: 92% 16

methyl 6-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrdzolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}-2-naphthoate  5.6 mg  9% of theory LC-MS (method 3): R_(t) =1.238 min. MS (ESIpos): m/z = 625 (M + H)⁺ 17

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3- iodobenzyl)carbamate19.5 mg  30% of theory LC-MS (method 3): R_(t) = 1.22 min. MS (ESIpos):m/z = 643 (M + H)⁺ 18

methyl [(6-chloropyridin-3- yl)methyl]{4,6-diamino-2- [6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate17.8 mg  32% of theory LC-MS (method 3): R_(t) = 1.14 min. MS (ESIpos):m/z = 552 (M + H)⁺ 19

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2,4-difluorobenzyl)carbamate 18.6 mg  32% of theory LC-MS (method 3): R_(t)= 1.19 min. MS (ESIpos): m/z = 553 (M + H)⁺ 20

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[4-(trifluoromethoxy)benzyl] carbamate 24.3 mg  40% of theory LC-MS (method3): R_(t) = 1.23 min. MS (ESIpos): m/z = 601 (M + H)⁺ 21

methyl (4- chlorobenzyl){4,6-diamino- 2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate18.3 mg  28% of theory LC-MS (method 3): R_(t) = 1.21 min. MS (ESIpos):m/z = 551 (M + H)⁺ purity: 84% 22

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2- methoxy-5-nitrobenzyl)carbamate 15.4 mg  25% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 592 (M + H)⁺ 23

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(5,6,7,8-tetrahydronaphthalen-2- ylmethyl)carbamate 20.9 mg  34% of theory LC-MS(method 3): R_(t) = 1.25 min. MS (ESIpos): m/z = 571 (M + H)⁺ purity:84% 24

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2,6-difluorobenzyl)carbamate   8 mg  14% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 553 (M + H)⁺ 25

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3- nitrobenzyl)carbamate18.5 mg  31% of theory LC-MS (method 3): R_(t) = 1.18 min. MS (ESIpos):m/z = 562 (M + H)⁺ purity: 94% 26

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2- fluoro-3-methylbenzyl)carbamate 18.9 mg  35% of theory LC-MS (method 3): R_(t) =1.21 min. MS (ESIpos): m/z = 551 (M + H)⁺ 27

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[3-(2-fluorophenoxy)benzyl] carbamate 22.7 mg  35% of theory LC-MS (method 3):R_(t) = 1.25 min. MS (ESIpos): m/z = 627 (M + H)⁺ 28

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(4- iodobenzyl)carbamate  22 mg  34% of theory LC-MS (method 3): R_(t) = 1.23 min. MS (ESIpos):m/z = 643 (M + H)⁺ 29

methyl [(4-bromo-1- naphthyl)methyl]{4,6- diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate15.4 mg  24% of theory LC-MS (method 3): R_(t) = 1.27 min. MS (ESIpos):m/z = 645 (M + H)⁺ 30

methyl (2-chloro-6- fluorobenzyl){4,6-diamino- 2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate  15 mg  25% of theory LC-MS (method 3): R_(t) = 1.19 min. MS (ESIpos):m/z = 569 (M + H)⁺ purity: 93% 31

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2- nitrobenzyl)carbamate13.8 mg  22% of theory LC-MS (method 3): R_(t) = 1.17 min. MS (ESIpos):m/z = 562 (M + H)⁺ purity: 91% 32

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[2-(trifluoromethyl)benzyl] carbamate 16.6 mg  27% of theory LC-MS (method3): R_(t) = 1.21 min. MS (ESIpos): m/z = 585 (M + H)⁺ 33

methyl 3-{1-[{4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]ethyl}benzoate   14 mg  20% of theory LC-MS (method 3): R_(t) = 1.20min. MS (ESIpos): m/z = 589 (M + H)⁺ purity: 86% 34

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3,5-dimethoxybenzyl)carbamate 16.6 mg  27% of theory LC-MS (method 3): R_(t)= 1.18 min. MS (ESIpos): m/z = 577 (M + H)⁺ 35

methyl 2-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}benzoate 18.1 mg  32% of theory LC-MS (method 3): R_(t) = 1. 71min MS (ESIpos): m/z = 575 (M + H)⁺ 36

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2- hydroxy-5-nitrobenzyl)carbamate  4.6 mg  8% of theory LC-MS (method 3): R_(t) =1.13 min. MS (ESIpos): m/z = 578 (M + H)⁺ 37

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[2-(difluoromethoxy)benzyl] carbamate 11.5 mg  15% of theory LC-MS (method3): R_(t) = 1.19 min. MS (ESIpOS): m/z = 583 (M + H)⁺ purity: 75% 38

methyl [3,5- bis(trifluoromethyl)benzyl] {4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate 20.7 mg  30% of theory LC-MS (method 3):R_(t) = 1.26 min. MS (ESIpos): m/z = 653 (M + H)⁺ purity: 94% 39

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2,4-dichlorobenzyl)carbamate 20.2 mg  29% of theory LC-MS (method 3): R_(t)= 1.23 min. MS (ESIpos): m/z = 585 (M + H)⁺ purity: 83% 40

methyl (4-cyano-2- fluorobenzyl){4,6-diamino- 2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate  16 mg  28% of theory LC-MS (method 3): R_(t) = 1.61 min MS (ESIpos):m/z = 560 (M + H)⁺ 41

methyl 4-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}-3- methoxybenzoate  4.9 mg  8% of theory LC-MS (method 3): R_(t)= 1.19 min. MS (ESIpos): m/z = 605 (M + H)⁺ 42

(4-{[{4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}phenyl)acetic acid  0.7 mg  1% of theory LC-MS (method 3): R_(t)= 1.09 min. MS (ESIpos): m/z = 575 (M + H)⁺ 43

methyl (3- bromobenzyl){4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 21.1 mg  35% oftheory LC-MS (method 3): R_(t) = 1.22 min. MS (ESIpos): m/z = 595 (M +H)⁺ purity: 84% 44

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidm-5-yl}(4- fluorobenzyl)carbamate  19 mg  32% of theory LC-MS (method 3): R_(t) = 1.18 min. MS (ESIpos):m/z = 535 (M + H)⁺ purity: 90% 45

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3-fluorobenzyl)carbamate 19.9 mg  36% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 535 (M + H)⁺ 46

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2-naphthylmethyl)carbamate  6.5 mg  11% of theory LC-MS (method 3): R_(t)= 1.22 min. MS (ESIpos): m/z = 567 (M + H)⁺ 47

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3,5-dimethylbenzyl)carbamate 25.8 mg  47% of theory LC-MS (method 3): R_(t)= 1.23 min. MS (ESIpos): m/z = 545 (M + H)⁺ 48

methyl [(5-chlorothiophen- 2-yl)methyl]{4,6-diamino-2- [6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate17.4 mg  31% of theory LC-MS (method 3): R_(t) = 1.21 min. MS (ESIpos):m/z = 557 (M+H)⁺ 49

methyl [2-chloro-4- (trifluoromethyl)benzyl]{4,6-diamino-2-[6-fluoro-3-(2- fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate 20.3 mg  32% of theory LC-MS (method 3):R_(t) = 1.24 min. MS (ESIpos): m/z = 619 (M + H)⁺ 50

methyl 4-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}benzoate 21.4 mg  34% of theory LC-MS (method 3): R_(t) = 1.16min. MS (ESIpos): m/z = 575 (M + H)⁺ purity: 91% 51

methyl [1-(3- chlorophenyl)ethyl]{4,6- diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate16.5 mg  28% of theory LC-MS (method 3): R_(t) = 1.24 min. MS (ESIpos):m/z = 565 (M + H)⁺ 52

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}{[6-(diethylamino)pyridin-3- yl]methyl}carbamate 3.1 mg  5% of theory LC-MS(method 3): R_(t) = 0.88 min. MS (ESIpos): m/z = 589 (M + H)⁺ 53

methyl (3- carbamoylbenzyl){4,6- diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 7.9 mg  14% of theory LC-MS (method 3): R_(t) = 1.06 min. MS (ESIpos):m/z = 560 (M + H)⁺ 54

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2,5-difluorobenzyl)carbamate 16.3 mg  29% of theory LC-MS (method 3): R_(t)= 1.19 min. MS (ESIpos): m/z = 553 (M + H)⁺ 55

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3,4-dimethylbenzyl)carbamate 14.1 mg  22% of theory LC-MS (method 3): R_(t)= 1.22 min. MS (ESIpos): m/z = 545 (M + H)⁺ purity: 87% 56

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3-methylbenzyl)carbamate   19 mg  36% of theory LC-MS (method 3): R_(t) =1.20 min. MS (ESIpos): m/z = 531 (M + H)⁺ 57

methyl (4- cyanobenzyl){4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 21.2 mg  39% oftheory LC-MS (method 3): R_(t) = 1.16 min. MS (ESIpos): m/z = 542 (M +H)⁺ 58

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2,6-dichlorobenzyl)carbamate  9.2 mg  16% of theory LC-MS (method 3): R_(t)= 1.21 min. MS (ESIpos): m/z = 585 (M + H)⁺ 59

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(1- phenylethyl)carbamate  9 mg  17% of theory LC-MS (method 3): R_(t) = 1.20 min. MS (ESIpos):m/z = 531 (M + H)⁺ 60

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2- fluoro-6-nitrobenzyl)carbamate 20.8 mg  33% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 580 (M + H)⁺ purity: 92% 61

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[4-(trifluoromethyl)benzyl] carbamate 19.6 mg  34% of theory LC-MS (method3): R_(t) = 1.23 min. MS (ESIpos): m/z = 585 (M + H)⁺ 62

tert-butyl 2-(4-{[{4,6- diamino-2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}phenyl)-4- methylpentanoate 15.2 mg  20% of theory LC-MS (method3): R_(t) = 1.32 min. MS (ESIpos): m/z = 687 (M + H)⁺ purity: 89% 63

methyl 2-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}-5-fluorobenzoate 14.5 mg  22% of theory LC-MS (method 3): R_(t)= 1.18 min. MS (ESIpos): m/z = 593 (M + H)⁺ purity: 90% 64

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(pyridin-2-ylmethyl)carbamate 5.69 mg  9% of theory LC-MS (method 3): R_(t) = 1.11min. MS (ESIpos): m/z = 518 (M + H)⁺ purity: 80% 65

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[2- methyl-3-(trifluoromethyl)benzyl] carbamate 20.3 mg  34% of theory LC-MS (method3): R_(t) = 1.24 min. MS (ESIpos): m/z = 599 (M + H)⁺ 66

methyl ([2- (cyclopropylcarbamoyl) pyridin-4-yl]methyl}{4,6-diamino-2-[6-fluoro-3-(2- fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1-yl]pyrimidin-5-yl}carbamate   17 mg  28% of theory LC-MS (method 3):R_(t) = 1.12 min. MS (ESIpos): m/z = 601 (M + H)⁺ 67

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[4- nitrobenzyl]carbamate  12 mg  21% of theory LC-MS (method 3): R_(t) = 1.18 min. MS (ESIpos):m/z = 562 (M + H)⁺ 68

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(2-methylbenzyl)carbamate 15.7 mg  27% of theory LC-MS (method 3): R_(t) =1.20 min. MS (ESIpos): m/z = 531 (M + H)⁺ purity: 92% 69

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(1-naphthylmethyl)carbamate 20.1 mg 351% of theory LC-MS (method 3): R_(t)= 1.23 min. MS (ESIpos): m/z = 567 (M + H)⁺ 70

methyl [{4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(methoxycarbonyl)amino](4-methoxyphenyl)acetate  8.8 mg  15% of theory LC-MS (method 3): R_(t)= 1.19 min. MS (ESIpos): m/z = 605 (M + H)⁺ 71

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[2-(trifluoromethoxy)benzyl] carbamate 12.5 mg  21% of theory LC-MS (method3): R_(t) = 1.22 min. MS (ESIpos): m/z = 601 (M + H)⁺ 72

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(3-methoxybenzyl)carbamate 19.7 mg 35% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 547 (M + H)⁺ 73

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}(4-methylbenzyl)carbamate 18.8 mg  33% of theory LC-MS (method 3): R_(t) =1.20 min. MS (ESIpos): m/z = 531 (M + H)⁺ 74

methyl (4- bromobenzyl){4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 23.3 mg  38% oftheory LC-MS (method 3): R_(t) = 1.22 min. MS (ESIpos): m/z = 595 (M+H)⁺75

methyl (2- bromobenzyl){4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 18.5 mg  31% oftheory LC-MS (method 3): R_(t) = 1.20 min. MS (ESIpos): m/z = 595 (M +H)⁺ 76

tert-butyl 3-chloro-4-{[{4,6- diamino-2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}(methoxycarbonyl)amino] methyl}benzoate  9.9 mg  15% of theory LC-MS(method 3): R_(t) = 1.28 min. MS (ESIpos): m/z = 651 (M + H)⁺ 77

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[1- (pyridin-2-yl)ethyl]carbamate  6.4 mg  12% of theory LC-MS (method 3): R_(t) = 1.17min. MS (ESIpos): m/z = 532 (M + H)⁺ 78

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5- yl}(pyridin-4-ylmethyl)carbamate  4.2 mg  6% of theory LC-MS (method 3): R_(t) = 0.93min. MS (ESIpos): m/z = 518 (M + H)⁺ purity: 76% 79

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[(6- methylpyridin-2-yl)methyl]carbamate 14.3 mg  23% of theory LC-MS (method 3): R_(t) =1.11 min. MS (ESIpos): m/z = 532 (M + H)⁺ purity: 87% 80

Methyl (biphenyl-2- ylmethyl){4,6-diamino-2-[6-fluoro-3-(2-fluorobenzyl)- 1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}carbamate 21.4 mg  27% of theory LC-MS (method 3): R_(t) = 1.21 min.MS (ESIpos): m/z = 585 (M + H)⁺ purity: 76% 81

methyl (3- cyanobenzyl){4,6-diamino- 2-[6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate 23.7 mg  44% oftheory LC-MS (method 3): R_(t) = 1.16 min. MS (ESIpos): m/z = 542 (M +H)⁺ 82

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}{4-[2-(trifluoromethyl)-1,3- thiazol-4- yl]benzyl}carbamate   10 mg  12% oftheory LC-MS (method 3): R_(t) = 1.27 min. MS (ESIpos): m/z = 668 (M+H)⁺purity: 81% 83

methyl 3-{[{4,6-diamino-2- [6-fluoro-3-(2- fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5- yl}(methoxycarbonyl)amino]methyl}benzoate 20.5 mg  36% of theory LC-MS (method 3): R_(t) = 1.17min. MS (ESIpos): m/z = 575 (M + H)⁺ 84

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[(2,6- dichloropyridin-3-yl)methyl]carbamate 13.4 mg  23% of theory LC-MS (method 3): R_(t) =1.18 min. MS (ESIpos): m/z = 586 (M + H)⁺ 85

methyl {4,6-diamino-2-[6- fluoro-3-(2-fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin- 1-yl]pyrimidin-5-yl}[3-(trifluoromethoxy)benzyl] carbamate 20.1 mg  33% of theory LC-MS (method3): R_(t) = 1.23 min. MS (ESIpos): m/z = 601 (M + H)⁺ 86

methyl (3- chlorobenzyl){4,6-diamino- 2-[6-fluoro-3-(2-fluorobenzyl)-1H- pyrdzolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate19.9mg  36% ofl theory LC-MS (method 3): R_(t) = 1.21 min. MS (ESIpos):m/z = 551 (M + H)⁺ 87

methyl (4-tert- butylbenzyl){4,6-diamino-2- [6-fluoro-3-(2-fluorobenzyl)-1H- pyrazolo[4,3-b]pyridin-1- yl]pyrimidin-5-yl}carbamate23.9 mg  40% of theory LC-MS (method 3): R_(t) = 1.27 min. MS (ESIpos):m/z = 573 (M + H)⁺

B. Assessment of Pharmacological Efficacy

The pharmacological effect of the compounds according to the inventioncan be shown in the following assays:

B-1. Vasorelaxant Action In Vitro

Rabbits are stunned by a blow to the neck and exsanguinated. The aortais removed, freed from adhering tissue and divided into rings of a widthof 1.5 mm. The rings are placed individually under an initial tension in5 ml organ baths with Krebs-Henseleit solution which is at 37° C., isgassed with carbogen and has the following composition (in each casemM): sodium chloride 119; potassium chloride: 4.8; calcium chloridedihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassiumdihydrogenphosphate: 1.2; sodium bicarbonate: 25; glucose: 10. Thecontractile force is determined with Statham UC2 cells, amplified anddigitalized using A/D transducers (DAS 1802 HC, Keithley InstrumentsMunich), and recorded in parallel on linear recorders. To obtain acontraction, phenylephrine is added to the bath cumulatively inincreasing concentration. After several control cycles, the substance tobe investigated is added in each further run in increasing dosage ineach case, and the height of the contraction achieved is compared withthe height of the contraction reached in the last preceding run. This isused to calculate the concentration needed to reduce the magnitude ofthe control value by 50% (IC₅₀ value). The standard administrationvolume is 5 μl; the DMSO content in the bath solution corresponds to0.1%.

Representative IC₅₀ values for the compounds according to the inventionare shown in the table below (Table 1):

TABLE 1 Example No. IC₅₀ [nM] 2 0.705 3 0.399 4 0.359 5 0.185 6 0.745 80.154B-2. Effect on a Recombinant Guanylate Cyclase Reporter Cell Line

The cellular activity of the compounds according to the invention isdetermined using a recombinant guanylate cyclase reporter cell line, asdescribed in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

Representative values (MEC=minimum effective concentration) for thecompounds according to the invention are shown in the table below (Table2):

TABLE 2 Example No. MEC [μM] 2 0.3 3 0.1 4 0.1 5 0.1 6 0.1 8 0.1B-3. Radiotelemetric Measurement of Blood Pressure on ConsciousSpontaneously Hypertensive Rats

A commercially available telemetry system from DATA SCIENCESINTERNATIONAL DSI, USA, is employed for the blood pressure measurementson conscious rats described below.

The system consists of 3 main components:

-   -   implantable transmitters (Physiotel® telemetry transmitter)    -   receivers (Physiotel® receiver) which are linked via a        multiplexer (DSI Data Exchange Matrix) to a    -   data acquisition computer.

The telemetry system makes it possible to continuously record bloodpressure, heart rate and body motions of conscious animals in theirusual habitat.

Animal Material

The investigations are carried out on adult female spontaneouslyhypertensive rats (SHR Okamoto) with a body weight of >200 g. SHR/NCrlfrom the Okamoto Kyoto School of Medicine, 1963 were a cross of maleWistar Kyoto rats with highly elevated blood pressure and female ratshaving a slightly elevated blood pressure and at F13 handed over to theU.S. National Institutes of Health.

After transmitter implantation, the experimental animals are housedindividually in type 3 Makrolon cages. They have free access to standardfeed and water.

The day/night rhythm in the experimental laboratory is changed by theroom lighting at 6.00 am and at 7.00 pm.

Transmitter Implantation

The telemetry transmitters TA11 PA-C40 used are surgically implantedunder aseptic conditions in the experimental animals at least 14 daysbefore the first experimental use. The animals instrumented in this waycan be employed repeatedly after the wound has healed and the implanthas settled.

For the implantation, the fasted animals are anesthetized withpentobarbital (Nembutal, Sanofi: 50 mg/kg i.p.) and shaved anddisinfected over a large area of their abdomens. After the abdominalcavity has been opened along the linea alba, the liquid-filled measuringcatheter of the system is inserted into the descending aorta in thecranial direction above the bifurcation and fixed with tissue glue(VetBonD™, 3M). The transmitter housing is fixed intraperitoneally tothe abdominal wall muscle, and the wound is closed layer by layer.

An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) is administeredpostoperatively for prophylaxis of infection.

Substances and Solutions

Unless indicated otherwise, the substances to be investigated areadministered orally by gavage in each case to a group of animals (n=6).The test substances are dissolved in suitable solvent mixtures, orsuspended in 0.5% strength Tylose, appropriate for an administrationvolume of 5 ml/kg of body weight.

A solvent-treated group of animals is employed as control.

Test Procedure

The telemetry measuring unit present is configured for 24 animals. Eachexperiment is recorded under an experiment number (Vyear month day).

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (1010 Receiver, DSI).

The implanted transmitters can be activated externally by means of anincorporated magnetic switch and are switched to transmission in therun-up to the experiment. The emitted signals can be detected online bya data acquisition system (Dataquest™ A.R.T. for Windows, DSI) and beappropriately processed. The data are stored in each case in a filecreated for this purpose and bearing the experiment number.

In the standard procedure, the following are measured for 10-secondperiods in each case:

-   -   systolic blood pressure (SBP)    -   diastolic blood pressure (DBP)    -   mean arterial pressure (MAP)    -   heart rate (HR)    -   activity (ACT).

The acquisition of measurements is repeated under computer control at5-minute intervals. The source data obtained as absolute value arecorrected in the diagram with the currently measured barometric pressure(Ambient Pressure Reference Monitor; APR-1) and stored as individualdata. Further technical details are given in the extensive documentationfrom the manufacturing company (DSI).

Unless indicated otherwise, the test substances are administered at 9.00am on the day of the experiment. Following the administration, theparameters described above are measured over 24 hours.

Evaluation

After the end of the experiment, the acquired individual data are sortedusing the analysis software (Dataquest™ A.R.T.™ Analysis). The blankvalue is assumed to be the time 2 hours before administration, and sothe selected data set encompasses the period from 7.00 am on the day ofthe experiment to 9.00 am the following day.

The data are smoothed over a presettable time by determination of theaverage (15-minute average) and transferred as a text file to a storagemedium. The measured values presorted and compressed in this way aretransferred into Excel templates and tabulated. For each day of theexperiment, the data obtained are stored in a dedicated file carryingthe number of the experiment. Results and test protocols are filed inpaper form sorted by numbers.

LITERATURE

-   Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and    Björn Lemme: Experimental heart failure in rats: effects on    cardiovascular circadian rhythms and on myocardial β-adrenergic    signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto:    Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270,    1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure,    Heart Rate, and Locomotor Activity in Spontaneously Hypertensive    Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4):    783-787, 1994

C. Working Examples of Pharmaceutical Compositions

The compounds according to the invention can be converted topharmaceutical formulations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg ofmagnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of the compound according to the invention, lactose andstarch is granulated with a 5% solution (w/w) of the PVP in water. Thegranules are dried and mixed with the magnesium stearate for 5 minutes.This mixture is pressed with a conventional tableting press (for tabletdimensions see above). The guide value used for the pressing is apressing force of 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

A single dose of 100 mg of the compound according to the inventioncorresponds to 10 ml of oral suspension.

Production:

The Rhodigel is suspended in ethanol; the inventive compound is added tothe suspension. The water is added while stirring. The mixture isstirred for about 6 h until the swelling of the Rhodigel is complete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. A single dose of 100 mg of thecompound according to the invention corresponds to 20 g of oralsolution.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate while stirring. The stirringoperation is continued until dissolution of the compound according tothe invention is complete.

i.v. Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically acceptable solvent(e.g. isotonic saline, glucose solution 5% and/or PEG 400 solution 30%).The solution is subjected to sterile filtration and dispensed intosterile and pyrogen-free injection vessels.

The invention claimed is:
 1. A compound of formula (I)

in which R¹ represents hydrogen or fluorine, R² represents hydrogen oramino, R³ represents (C₁-C₄)-alkyl, R⁴ represents hydrogen,(C₁-C₄)-alkyl or (C₁-C₄)-alkoxycarbonyl, R⁵ represents phenyl,tetrahydronaphthalenyl, naphthyl or 5- to 10-membered heteroaryl, wherephenyl, tetrahydronaphthalenyl, naphthyl and 5- to 10-memberedheteroaryl may be substituted by 1 to 3 substituents independently ofone another selected from the group consisting of halogen, nitro, cyano,difluoromethyl, trifluormethyl, (C₁-C₆)-alkyl, hydroxy, difluoromethoxy,trifluoromethoxy, (C₁-C₄)-alkoxy, amino, mono-(C₁-C₄)-alkylamino,di-(C₁-C₄)-alkylamino, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl,aminocarbonyl, mono-(C₁-C₄)-alkylaminocarbonyl,di-(C₁-C₄)-alkylaminocarbonyl, (C₃-C₇)-cycloalkylaminocarbonyl,phenylsulfonylmethyl, phenyl and phenoxy, where (C₁-C₆)-alkyl may besubstituted by one substituent independently of one another selectedfrom the group consisting of hydroxycarbonyl and (C₁-C₄)-alkoxycarbonyl,and where phenyl and phenoxy may be substituted by 1 to 3 substituentsindependently of one another selected from the group consisting ofhalogen and cyano, R⁶ is (C₁-C₆)-alkyl or benzyl, where (C₁-C₆)-alkyl issubstituted by one trifluoromethyl substituent, where (C₁-C₆)-alkyl maybe substituted by 1 to 3 fluorine substituents, and where benzyl issubstituted by 1 to 3 fluorine substituents, or a salt thereof.
 2. Thecompound of claim 1 in which R¹ represents hydrogen or fluorine, R²represents hydrogen or amino, R³ represents (C₁-C₃)-alkyl, R⁴ representshydrogen or methyl, R⁵ represents phenyl, thienyl, thiazolyl, pyridyl orquinolyl, where phenyl, thienyl, thiazolyl, pyridyl and quinolyl may besubstituted by 1 to 3 substituents independently of one another selectedfrom the group consisting of fluorine, chlorine, nitro, cyano,difluoromethyl, trifluoromethyl, (C₁-C₆)-alkyl, hydroxy,difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, amino, methylamino,ethylamino, dimethylamino, diethylamino, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, cyclopropylamninocarbonyland cyclobutylaminocarbonyl, where (C₁-C₆)-alkyl may be substituted byone substituent independently of one another selected from the groupconsisting of hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl, R⁶represents 3,3,3-trifluoroprop-1-yl, 3,3,4,4,4-pentafluorobut-1-yl orbenzyl, where benzyl is substituted by 1 or 2 fluorine substituents, ora salt thereof.
 3. The compound of claim 1 in which R¹ representshydrogen or fluorine, R² represents hydrogen or amino, R³ representsmethyl, ethyl or isopropyl, R⁴ represents hydrogen, R⁵ representsphenyl, where phenyl may be substituted by 1 fluorine substituent, R⁶represents 2-fluorobenzyl, or a salt thereof.
 4. A process for preparingthe compound of claim 1 comprising reacting a compound of formula (II)

in which R¹, R² and R⁶ each have the meanings given in claim 1 in thepresence of a base with a compound of formula (III)

in which R³ has the meaning given in claim 1 to give a compound offormula (IV)

in which R¹, R², R³ and R⁶ each have the meanings given in claim 1,reacting the compound of formula (IV) with a compound of formula (V)

in which R⁴ and R⁵ each have the meanings given in claim 1 and X¹represents a leaving group and optionally converting the resultingcompounds of formula (I) with the appropriate (i) solvents and/or (ii)acid or base into a salt thereof.
 5. A pharmaceutical compositioncomprising the compound of claim 1 and an inert, nontoxic,pharmaceutically suitable excipient.
 6. The pharmaceutical compositionof claim 5, further comprising an active ingredient selected from thegroup consisting of an organic nitrate, an NO donor, a cGMP-PDEinhibitor, an antithrombotic agent, a hypotensive agent and a lipidmetabolism modifier.
 7. A method of treatment of hypertension comprisingadministering to a human or animal in need thereof an effective amountof at least one compound of claim
 1. 8. A method of treatment ofhypertension comprising administering to a human or animal in needthereof an effective amount of at least one pharmaceutical compositionof claim
 5. 9. The process of claim 4, wherein X¹ is mesylate, tosylate,or a halogen.
 10. The process of claim 9, wherein X¹ is a halogen.